New pregnene and pregnadiene compounds and processes for preparing the same



United States Patent 3,121,078 NEW PREGNENE AND PREGNADIENE COM- POUNDSAND PROCESSES FOR PREPAR- IN G THE SAME Han-y L. Slates, Madison, andNorman L. Wendler, Summit, N.J., assi'gnors to Merck & Co., Inc.,Rahway, N.J., a corporation of New Jersey No Drawing. Filed Nov. 7,1957, Ser. No. 694,929 15 Claims. (Cl. 260239.5)

This invention relates generally to novel steroid compounds and toprocesses for preparing the same. More particularly, it is concernedwith 2lhydroxy-16methyll1 oxygenated 4,16 pregnadiene 3,20 dionecompounds. It is also concerned with the preparation of the novel 21hydroxy 11 oxygenated 4 pregnene 16a, l7u-methyleneazo-3,20-dionecompounds produced as intermediates in the synthesis ofZI-hydroxy-l-methyl-l 1- oxygenate-d 4,16 pregnadiene 3,20 dionecompounds. These compounds are active medicinal adjuncts for reducingthe abnormally high eosinophil count accompanying many diseases.

These novel 2l-hydroxy-16-methyl l1-oxygenated-4,16-pregnadiene-3,20-dione compounds subject of the present invention, maybe chemically represented as follows CHzOR RT lfiCE.

CHzOR" wherein R, R and R" are as above.

It has been found that the 2l-hydroxy-1l-oxygenated-4,l6-pregnadiene-3,20-dione may be caused to react With diazomethane toyield 21-hydroxy-1l-oxygenated-4-preg-Irene-16a,17amefihyleneazo-3,20-dione having the structural formula W ITwherein R, R and R are as above. The compound thus obtained may then beheated to form the novel 21- 3,121,078 Patented Feb. 11, 1964 icehydroxy 16 methyl 11 oxygenated 4,16 pregnadiene-3,2()-dione compoundswhich may 'be identified by the following formula CHZOR" wherein R, Rand R" are as above.

The compounds employed as starting materials in the process of thisinvention are conveniently prepared by reacting anl7a,2l-dihydroxy-l1-oxygenated-4-pregnene-3,20-dione-21-acetate-3,20-disemicarbazone with hot acetic acid followedby removal of the semicarbazide groups with pyruvic acid. The21-hydroxy-11-oxygenated-4,16- pregnadiene-3,20-dione starting materialsinclude 21-hydroxy-4,l6-pregnadienes-3,l1,20-trione and esters thereofand particularly 2l-lower hydrocarbon carbonyl esters as for example21-hydroxy-4,l6-pregnadiene-3,11,20-trione 21-henzoate;2l-hydroxy-4,l6-pregnadiene-3,ll,20r trione 21-lower alkanoates such as21-hydroxy4,16-pregnadiene-3,l1,20-trione 2-l-acetate;21-hydroxy-4,16-pregnadiene-3,l1,20-trione 21-propionate;21-hydroxy-4,16- pregnadiene-3,11,20-trione 2l-alkyl ethers;11,21-dillydroxy-4,16-pregnadiene-3,20-dione and esters thereof andparticularly 21-lower hydrocarbon carbonyl esters as for example, 11,21dihydroxy 4,16 pregnadiene 3,20- dione 21-benzoate;11,21-dihydroxy-4,16-pregnadiene-3, ZO-dione 21-lower alkanoates such as11,2l-dihydroxy-4, l6-pregnadiene-3,20-dione 21-acetate;11,21-dihydroxy-4, l6 pregnadiene 3,20-dione 21 propionate; 11,21dihydroxy-4,l6-pregnadiene-3,20-dione 21-alkyl ethers; 9afluoro 21hydroxy 4,16 pregnadiene 3,11,20-trione and esters thereof andparticularly 21-lower hydrocarbon carbonyl esters as for example9a-fluoro-2l-hydroxy-4, 16-pregnadiene-3,11,20-trione 21-benzoate;9oc-flUOI'O-2lhydroxy-4,l6-pregnadiene-3,11,20-trione 21-loweralkanoates such as 9u-fluoro-21-hydroxy-4,l6-pregnadiene-3,11,

' 20-trione ZI-acetate;9a-fluoro-21-hydroxy-4,16-pregnadiene-3,11,2()-trione 2l-propionate;9a-fiuoro-2l-hydroxy- 4,16-pregnadiene-3,11,20-trione 2l-alkyl ethers;9afiuoro 11,21 dihydroxy 4,16 pregnadiene 3,20- dione and esters thereofand particularly 21-lower hydrocarbon carbonyl esters as for example9oz-fluoro-1L2ldihydroxyt,l6-pregnadiene 3,20-dione 21-benzoate;9ozfiuoro 11,21 dihydroxy 4,16 pregnadiene 3,20- dione 2l-loweralkanoates such as 9/x-fiuoro-1L21-dihydroxy 4,16 pregnadiene 3,20 dione21 awtate; 9afluoro 11,21 dihydroxy 4,16 pregnadiene 3,20- dione2l-propionate; and 9a-fluoro-ll,2l-dihydroxy-4,l6-pregnadiene-3,20-dione 2l-alkyl others.

In accordance with the present invention, any of the starting materialsenumerated above is reacted with diazomethane in an inert solvent toform the corresponding methyleneazo compounds, namely, 2l-hydroxy-4-pregnene-lrx,17a-methyleneazo-3,l1,20-trione and esters thereof andparticularly 21-lower hydrocarbon carbonyl esters as for example21-hydroxy-4-pregnene-16a,17amethyleneazo-3,11,20-trione 21- benzoate;21-hydroxy-4- pregame-16a,17u-methyleneazo-3 ,1 1,20-trione 21-loweralkanoates such as21-hydroxy-4-pregnene-16a,17u-methyleneazo-3,l1,20-trione Zl-acetate; 2l-hydroxy-4-pregnene-l6a,17a-methyleneazo-3,11,20-trione 21-alkylethers; 115,2l-dihydroxy 4 pregnene ;,170; methyleneazo- 3,20-dione andesters thereof and particularly, lower hydrocarbon carbonyl esters asfor example, 11,8,21-dihy- 3 droxy-4-pregnene-16a,17a-methyleneazo3,20-dione 21- benzoate;ll/3,21-dihydroxy-4-pregnene-16oz,17u-methyleneazo-3,20-dione 2l-loweralkanoates such as 115,21-

dihydroxy-4-pregnene-l6a,17a methyleneazo 3,20-dione 21-acetate; 1 15,2l-dihydroxy-4-pregnene-1 6oz, 17u-methyleneazo-3,20-dione 21-propionate;1 15,2l-dihydroxy-4-pregnene-l6a,l7a-methyleneazo-3,20-dione 21-a1kylethers; 9afluoro-2l-hydroxy-4 pregnene l6oc,17oc methyleneazo-3,11,20-trione and esters thereof and particularly 21-lower hydrocarboncarbonyl esters as for example 9a-fluoro 2l-hydroxy-4-pregnene-16a,17amethyleneazo 3,11,20- trione 21 benzoate; 90cfiuoro-21-hydroxy-4-pregnene- 16a,l7a-methyleneazo-3,11,20 trione 21lower alkanoate such as 9a-fluoro-21-hydroxy-4-pregnene-1611,17-methyleneazo-3,11,20-trione 21-acetate;9a-fluoro-2lhydroxy-4-pregnene-16a,17a-methyleueazo-3,11,20 trione21-alkyl ethers; 9a-fluoro-115,21-dihydroxy-4-pregnene-16a,17a-methyleneazo-3,20-dione and esters thereof and particularlylower hydrocarbon carbonyl esters as for example 9oc-fll10I'O-l15,21-dihydroxy-4-pregnene-16a,17amethyleneazo-3,20-dione 21-benzoate;9oz-flllOI'O-1LB,21- dihydroxy-4-pregnene-16u,17ec-methyleneazo-3,20dione 21-lower alkanoates such as 9a-fluoro-l1fi,2l-dihydroxy-4-pregnene-16a,17a-methyleneazo-3,20-dione ZI-acetate;9u-fluoro-11,3,21-dihydroxy-4-pregnene-16a,17oc methyleneazo3,20-dione21-propionate;9afluoro-11,3,21-dihydroy-4-pregnene-16a,17a-rnethyleneazo-3,20-dione2l-alkyl esters.

Upon heating any of the above enumerated methyle'neazo compounds, thecorresponding 16-methyl derivative is formed with evolution of nitrogen.The compounds thus formed include 2l-hydroxy-l6-n1ethy1-4,16-pregnadiene-3,11,20-trione and esters thereof and particularly 2l-lowerhydrocarbon carbonyl esters for example 21 hydroxy-16-methy1-4,16-pregnadiene-3,11,20 trione 21-benzoate;2l-hydroxy-il6-methyl-4,16-pregnadiene-3,11,20-trione 21-benzoate;21-lower alkanoates such as21-hydr0xy-16-methyl-4,16-pregnadiene-3,11,20- trione 21 acetate; 21hydroxy-16-methyl-4,16-pregnadiene-3,ll,20-trione 21-propionate;21-hydroxy-16-methyl 4,16 pregnadiene 3,11,20 trione 21 alkyl ethers;11,2l-dihydroxy-16-methyl-4-16-pregnadiene 3,20 dione and esters thereofand particularly 21-lower hydrocarbon carbonyl esters as for example,11-21-dihydroxy 16 methyl-4,16-pregnadiene-3,20-dione 21 benzoate; 11,21-dihydroxy-16-methyl-4,l6-pregnadiene-3,20- dione 21-loweralkanoates such as 11,21-dihydroxy-l6- methyl-4,16-pregnadiene 3,20-dione ZI-acetate; 11,2 dihydroxy-16-methyl-4,16-pregnadiene 3,20 dione21- propionate; 11,21 dihydroxy 16 methyl-4,16-pregnadiene-3,20-dione2'1-aJkyl ethers; 9a-fluoro-2l-hydroxy-16-methyl-4,l6-pregnadiene-3,l1,20-trione and esters thereof andparticularly 21-lower hydrocarbon carbonyl esters as for example9a-fiuoro-21-hydroxy-l6-methyl-4, 16-pregnadiene-3,11,20-trione2l-benzoate; 9a-fiuoro-21- hydroxy-16-methyl-4,16-pregnadiene 3,11,20trione 21- lower alkanoates such as 9a-fiuoro-21-hydroxy-16-methyl4,16-pregnadiene-3,11,20-trione 21-acetate; 9cc-flI1OIO-21-hydroxy-16-methyl-4,16-pregnadiene-3, 11,20 trione 21- propionate;9u-fluoro-21-hydroxy-16-methyl-4,16-pregnadiene-3,11,20-trione 21-alkylethers; 9a-fluoro-1l,21-dihydroxy-16-methyl-4,16 pregnadiene 3,20-dioneand esters thereof and particularly 21-lower hydrocarbon carbonyl estersas for example, 9a-fil101'O-1L2l-dihYdrOXY-l6-methyl-4,l6-pregnadiene-3,20-dione 21-benzoate;9afiuoro-l1,21-dihydroxy-16 methyl 4 16 pregnadiene- 3,20-dione 21-loweralkanoates such as 9m-fluoro-11,21- dihydroxy-l6-methyl 4,16 pregnadiene3,20-dione 21- acetate; 9a-fluoro 11,21 dihydroxy -16 methyl 4,16-pregnadiene-3,20-dione 21-propionate; and 9a fluoro- 11,21-dihydroxy-16methyl 4,16-pregnadiene 11,21-

diol-3,20-dione 21-alkyl ethers. Any of the above steroids having analkauoate in the 2-position can be converted to the alcohol byhydrolysis by potassium bicarbonate in an aqueous solution.

In accordance with one embodiment of the present invention a startingmaterial such as 21-hydroxy-4,16- pregnadiene-3,11,20-trione 21-acetaceis added to an inert solvent such as tetrahydrofuran and an excess ofdiazomethane is added. The solvent is removed by concentration and the'21-hydroxy-4-pregnene-160:,17 methyleneazo-3,1=1,20-trione 21'aoetateis crystallized from ethyl acetate or an acetone-ether mixture. Thealcohol, namely, 2l-hydroxy-4-pregnene-l6a,Nan-methyleneazo-3,ll,20-trione may be obtained by hydrolysis of 21-hydroxypregnene :,170: methyleneazo 3,11,20- trione 21-acetate in aqueousalcohol solution with potassium bicarbonate.

Heating 21-hydroxy-4-pregnene-2Fol-16a,17w-methyleneazo-3,11,20-trioneill-acetate until nitrogen evolution ceased results in the21-hydroxy-1'6-rnethyl-4,16-pregna-' diene-3,11,20-trione 21-acetate.After cooling the melt can be crystallized from ethyl acetate or anacetoneether mixture. The21-hydroxy-16-methyl-4,16-pregnadiene-3,11,20-trione 21-acetate can behydrolyzed with potassium carbonate in an aqueous alcohol medium to form21-hydroxy 16-methyl-4,16-pregnadiene-3,11,20- trione.

The following examples are to be understood as illusl Qj .Qj I f f To2.0 g. of 21-hydroxy-4,16'pregn'adiene-3,11,20-trione 21-acetateprepared as described herein below in 50 =ml..of

azo methane. The reaction mixture Was allowed to stand at ca. 20 C. for6 hours and then concentrated in vacuo.

The residue was crystallized from ethyl acetate to yield 1.5 g. of2l-hydroxy-4-pregnene-16a,17u-methyleneazo- 3,11,20 trione 21-acetateM.P. 176 C. with gas 1 evolution. a

A sample of this latter substance was hydrolyzed in aqueous alcohol withpotassium bicarbonate to form 21-hydroxy-4-pregnene-l6a,17u-methyleneazo 3,11,20-trione.

The 21 hydroxy-4-pregnene-21-ol-16a,17a-methyleneazo-3,1l,20-trione21-acetate obtained as above was heated to 180-185 C. in vacuo 1 mm.)and held at this temperature until the evolution of nitrogen had ceased.After cooling, the melt was crystallized from ethyl acetate to yield2l-hydroxy-16-rnethyl-4,16-pregnadiene-3,l1,20- trione 21-acctate M.P.171l73 C., Mnax. 241 me, E% 526.

The starting material 21-hydroxy-4,16-pregnadiene- 3,11,20-trione21-acetate may be prepared as follows:

A solution of 5.0 g. of 170:,21-dihydroxy-4-pregnene- 3,20-dione21acetate-3,20-disemicarbazone in 100 ml. of acetic acid containing 5ml. of acetic anhydride was refluxed in a nitrogen atmosphere for 1hour. The pale yellow to red reaction mixture was concentrated in vacuoto a volume of 60 ml. and treated with 30 ml. of water and 15 ml. ofpyruvic acid, and allowed to stand at room temperature for 40 hours andat 60 for 2 hours. After dilution with water, the product was extractedwith chloroform and the chloroform solution was washed with water, 5%potassium bicarbonate, water, and dried over magnesium sulfate. Thesolvent was removed in vacuo and the residue was chromatographed on 200g. of neutral alumina and elution with benzene afforded, aftercrystallization from acetone-ether, 1.37 g. (38%) of 21-hydroxy-4,16-pregnadiene-3,l1,20-trione 2l-aceta-te M.P. 186187 C.

i r on g g my, e=25,200

Analysis calculated for C H O C, 71.85; H, 7.34. Found: C, 71.96; H,7.26.

Example 2 CHzOAO CH2OAG (i=0 I N=N HO HO\ lfi F F O: V 0:

l 33 5 N=N 3:0 HO J Ho Afr...

CHaOH =0 ITO-[ l OH: l/|

T0 2.9 g. of 9a-fluoro-115,21-dihydroxy-4,16-pregnadiene-3,20-dione21-acetate prepared as described hereinafter in 100 ml. of drytetrahydrofuran was added a threefold excess of d-iazornethane. Thereaction mixture was allowed to stand at ca. 20 C. for about 16 hoursand then concentrated in vacuo. The residue was crystallized fromacetone-ether to yield 3.0 g. of 9oc-fil1OI0-11fi,21-dihydroxy-4-pregnene-l6a,17armethyleneaZo-3,20 dione 2l-acetate M.P.186-187 C. with gas evolution.

A sample of 9a-fluoro-115,21-dihydroxy-4-pregnene-16a,17a-methyleneazo-3,20-dione 2l-acetate was hydrolized in aqueousalcohol with potassium bicarbonate to yield fiuoro115,21-dihydroxy-4-pregnene-16a,17amethyleneazo-3,20-dione.

The 9a-fluoro-115,21-dihydroxy-4 pregnene-16a,17amethyleneazo-3-,20-d-ior1e 21-acetate obtained as above was heated to190195 C. in vacuo 1 mm.) and held at this temperature until nitrogenevolution ceased. After cooling, the melt was crystallized twice fromacetoneet her to give 1.3 g. of 9a-fiu0ro-l15,21-dihydroxy-l6-methyl-4,l6-pregnadiene-3,20-dione 2l-acetate M.P. 179- 181 C., Amax.242a, E% 550.

A sample of 9a-fluoro-115,21-dihydroxy-16-methyl-4,16-pregnadiene-3,20Pdione 21-acetate was hydrolyzed in aqueous alcoholwith potassium bicarbonate to form 911- fluoro-l 15,2 l-dihydroxy-4, l6-pregnadiene-3,20-dione.

9a-fluoro-l 1,8,21-dihydroxy-4, 1 6-p1'egnadiene- 3,20-dione 21-acetate,the starting material for this example, may be prepared as follows:

To a solution of 5.0 g. of9oc-fluoro-l1fi,l7a,21-trihydroxy-4-pregnene-3,20-dione ZI-aoetate in200 ml. of methanol was added a solution of 5.0 g. of semicarbazide and3.0 g. of semicarbazide hydrochloride in 10 ml. of water. The reactionmixture was heated under'refluxfor 4 hours, then cooled to ca. 5 C. Thecrystalline product was isolated by filtration to yield 5.6 g. of9oc-fll101O-11/3, 17a,21-trihydroxy-4-pregnene-3,20-dione2l-aceta-te3,20- disemicarbazone; M.P. 220 C. with decomposition;

267 mp, E% 571 A solution of 5.0 g. of9a-fiuoro-l1fi,l'7a,2l-trihydroxy-4.-pregnene-3,20-dione 2l acetate3.,20 disemicarbazone in ml. of acetic acid containing 2 ml. of aceticanhydride was refluxed in a nitrogen atmosphere for 1 hour. The reactionmixture was concentrated in vacuo to a volume of 60 m1. and treated with30 ml. of Water and 15 ml. of pyruvic acid, and allowed to stand at roomtemperature for 18 hours and 2 hours at 60 C. After dilution with water,the product was extracted with chloroform and the chloroform solutionwas washed with water, 5% potassium bicarbonate, water, and dried overmagnesium sulfate. The solvent was removed in vacuo and the residue waschromatographed on 200 g. of neutral alumina and elution :withbenzene-chloroform mixtures alforded after crystallization fromacetone-ethanol 0.8 g. of 9a-fluoro-l18,21-dihydroxy-4,l'6-pregnadiene-3, 20-dione 2l-acetate, M.P. 184-186"C.,

It should be understood that various changes may he made in the presentprocess as herein described without alfecting the results attained.Thus, various modifications of conditions as to time, temperature, etc.and various changes in procedure diflering from those herein given asillustrative of the preferred embodiments of this invention may be madeWithout departing from the scope thereof. Accordingly, the scope of ourinvention is to be determined in accordance with the prior art and theappended claims.

7 I We claim: 1. A compound of the formula:

I HO /\A CH3 only wherein R is selected from the group consisting ofhydrogen and lower alkanoyl radicals.

2. 9a-fiuoro-115,2l-dihydroxy-lG-methyl 4,16 pregnadiene-3,20-dione.

3. 9m-fluoro-11 8,2l-dihydroxyd6-methyl 4,16 pregnadiene-3,20-dione2l-lower hydrocarbon carbonyl group.

4. A compound of the formula:

wherein R is selected from the group consisting of hydro- CHzOR" whereinR is selected from the group consisting of hydrogen and fluorine, R isselected from the group consisting of keto and hydroxy and R" isselected from the group consisting of hydrogen, and a lower hydrocarboncarbonyl group with diazomethane to form a compound of the formula:

CH2OR" 10. The process which comprises reacting 2l-hydroxy4,l6-pregnadiene-3,'l1,20-trione with diazomethane to form2l-hydroxy-4-pregnene 16u,17a methyleneazo-3,

115,20-trione and heating the latter compound to form21-hydroXy-16-methyl-4, 16-pregnadiene-3 ,1 1,20-trione.

'11. The process which comprises reacting 2l-hydroxy-'4,l6-pregnadiene-3,11,20-trione 2l-lower hydrocarbon carbonyl withdiazomethane to form21-hydroXy-4-pregnene-l6a,l7a-rnethy1eneazo-3,11,8,20-trione 2l-lowerhydrocarbon carbonyl and heating the latter compound to form 2l-hydroxyl6 methyl-4,16-pregnadiene-3,ll,20- trione 21-1ower hydrocarboncarbonyl.

12. The process which comprises reacting 2l-hydroxy-4,l6-pregnadiene-3,l1,20-trione 21-lower hydrocarbon carbonyl withdiazomethane to form 21-hydroXy-4-pregnone-1 6a, 17u-met'hyleneazo-3, 11 5,20-trione 21-lower hydrocarbon carbonyl and heating the lattercompound to 7 form 21-hydroxy 16 methyl-4,16-pregnadiene-3,l1,20- trione21-lower hydrocarbon carbonyl and hydrolyzing the latter compound toform 2l-hydroXy-l6-methyl-4,16-pregnadiene-3, 1 1,20-trione.

13. The process which comprises reacting 9a-flnoro-11,8,21-dihydroXy-4,16-pregnadiene-3,20-dione with diazomethane to form9a-flnoro-1113,21-dihydroxy-4-pregnene- 16a,17a-methyleneazo-3,ZO-dioneand heating the latter compound to form9a-fluoro-11,8,2l-dihydroxy-16-methyl- 4,16-pregnadiene-3,ZO-dione.

14. The process which comprises reacting 9oc-fi1l0l'0- V 113,2l-dihydroxy-4,16-pregnadiene 3,20 dione 2l-lower hydrocarbon carbonylwith diazomethane to form fiuoro-11fl,21-dihydroxy 4-pregnene l6a,17amethyleneaZo-3,20-dione 21-lower hydrocarbon carbonyl and heating thelatter compound to form 9a-fiuo-ro-l1p321- dihydroxy-l6 methyl 4,16pregnadiene-3,20-dione 21- lower hydrocarbon carbonyl.

15; The process which comprises reacting 9a-fluoro-1lfi,2J1-dihydroxy-4,l6-pregnadiene 3,20-dione 2l-lower hydrocarboncarbonyl with diazomethane to form 9afluoro-l15,21-dihydroXy-4-pregnene16a,l7a-methyleneazo-3,20-dione 2l-lower hydrocarbon carbonyl, heatingthe latter compound to form 9a-fiuoro-l1,8,21-dihydroxy-16-methyl-4,16-pregnadiene-3,2(}-dione 21-lower hydrocarbon carbonyl andhydrolyzing the latter compound to form 9afiuoro115,21-dihydroxy16-methyl-4,16-pregna diene-3,20-d ione.

References Cited in the file of this patent UNITED STATES PATENTS MullerMay 21, 1957 OTHER REFERENCES Noller: Textbook of Organic Chemistry(1951), page 316, W. B. Saunders Co., Philadelphia, Pa.

1. A COMPOUND OF THE FORMULA:
 4. A COMPOUND OF THE FORMULA: